Asthma is an inflammatory disease of the airways that affects millions of people globally. Recent studies have shown that asthma remains inadequately controlled in many patients, despite treatment in accordance with guidelines. There is clearly an unmet need for the effective and safe treatment of patients with asthma who remain symptomatic despite optimized standard treatment. A strong association exists between asthma control/hospitalization and asthma-related mortality. While all patients are susceptible to exacerbations, uncontrolled asthma increases the risk of an exacerbation being life-threatening or fatal.
Chronic obstructive pulmonary disease (COPD) is common world-wide. The prevalence of the disease continues to grow in most industrialized nations. It is mostly associated with cigarette smoking. Although COPD is a leading cause of illness and death, its recognition as a public health problem has been slow to evolve despite the rising mortality rate for COPD. Additionally, COPD imparts substantial economic burden on individuals and society.
The treatment of interstitial lung disease such as interstitial pulmonary fibrosis (IPF), Sarcoidosis, hypersensitivity pneumonitis (HP), and bronchiolitis obliterans with organizing pneumonitis (BOOP) basically rests on the use of systemic corticosteroids. This treatment is effective in controlling some of the inflammation but induces serious side effects and does not reverse underlying fibrotic changes. Immunosupressive agents such as cyclophosphamide and azathioprine are sometimes tried in severe IPF but their therapeutic values are unproven and at most, very limited (Zisman D et al. Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids. Chest 2000, 117: 1619-1626). In essence, lung fibrosis is usually progressive and untreatable, with most IPF patients dying of this condition. The above suggest there is still a need for a therapy that offers benefit to current treatments of respiratory diseases such as asthma and COPD. Inhalation drug delivery has been an attractive approach for drug administration and treatment of pulmonary diseases since inhaled drugs are localized to the target organ, which generally allows for a lower dose than is necessary with systemic delivery.
Various techniques and devices may be used to deliver a drug to the lung such as metered-dose inhaler (MDI), dry powder inhaler (DPI) and nebulizer. Each technique and device has advantages, challenges and limitations. For example, MDIs which contained chlorofluorocarbons (CFC) to deliver the drug and many of these have been phased out over the recent years. Nebulization may be suitable in a hospital setting however the administration of a drug requires particular physico-chemical properties of the active agent and may involve substantial patient and professional time and as such reduce patient compliance.
DPI preparations have to overcome various difficulties for effective drug delivery. For example, the small size of the inhalable particles subjects them to forces of agglomeration and cohesion, resulting in poor flow performance and non-uniform dispersion. Pharmaceutical preparations for DPI therefore often require that the active ingredient be blended with a carrier to improve flow properties. The efficiency of a DPI powder is therefore often dependent on the carrier characteristics. Although the manufacture of a suitable drug product and the effective performance of DPI products are dependent on the inhaler device, drug deposition in the lung is also dependant on many factors including the size, and the aerodynamics the physicochemical properties of the active ingredient particles.
In addition, various agents are now used with the active ingredient and/or the carrier or excipient to modify the “performance” of the DPI preparations to improve flow, reduce inter-particulate adhesion and reduce moisture effects, and thereby achieve improved particle deposition in lungs. For example, the addition of magnesium stearate to inhalation powders is reported to improve aerosol performance and increase moisture resistance.
Furthermore, it is often desirable to control the moisture content in the active pharmaceutical ingredient (API), and optionally the carriers, excipients, packaging materials (primary and secondary), and the manufacturing environment. Moisture sensitivity may require special manufacturing processes/treatments for packaging materials, especially for those in direct content with the pharmaceutical preparation.